A Comprehensive Review of Natural Flavonoids with Anti-SARS-CoV-2 Activity

The COVID-19 pandemic caused by SARS-CoV-2 has majorly impacted public health and economies worldwide. Although several effective vaccines and drugs are now used to prevent and treat COVID-19, natural products, especially flavonoids, showed great therapeutic potential early in the pandemic and thus attracted particular attention. Quercetin, baicalein, baicalin, EGCG (epigallocatechin gallate), and luteolin are among the most studied flavonoids in this field. Flavonoids can directly or indirectly exert antiviral activities, such as the inhibition of virus invasion and the replication and inhibition of viral proteases. In addition, flavonoids can modulate the levels of interferon and proinflammatory factors. We have reviewed the previously reported relevant literature researching the pharmacological anti-SARS-CoV-2 activity of flavonoids where structures, classifications, synthetic pathways, and pharmacological effects are summarized. There is no doubt that flavonoids have great potential in the treatment of COVID-19. However, most of the current research is still in the theoretical stage. More studies are recommended to evaluate the efficacy and safety of flavonoids against SARS-CoV-2.


Introduction
COVID-19 is a global disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a high morbidity and mortality rate. As of November 2022, COVID-19 has spread to 222 countries with more than 600 million confirmed cases and more than 6.5 million cumulative deaths [1]. The COVID-19 outbreak not only endangers human health and livelihoods, but also has a huge impact on global public health systems and economic development.
SARS-CoV-2 is a positive-stranded RNA virus with a characteristic coronavirus spine protein on its outer surface that is capable of droplet transmission [2][3][4]. The viral structure of SARS-CoV-2 has a high degree of similarity to SARS-CoV and MERS-CoV, and it is similarly a zoonotic virus with a long incubation period and high transmission rate [2,[5][6][7]. SARS-CoV-2 is highly mutagenic, and there are currently four mutant strains, Alpha, Beta, Gamma, and Delta, with the newly discovered Omicron mutant strain becoming a major global disease and causing strain in just a few months due to its strong infectious and immune-escaping ability [8][9][10][11]. Some common symptoms include fever, headache, shortness of breath, fatigue, cough, nausea, vomiting, diarrhea, and nasal congestion [12][13][14]. Most infected patients are from mild to moderate and do not require special treatment, but those with underlying conditions, such as heart disease, lung disease, and diabetes, as well as the elderly, are more likely to become seriously ill and have a higher mortality rate [13,[15][16][17].

Structure and Classification of Flavonoids
Flavonoids are a series of polyphenolic compounds found in various plants that have a benzo-γ-pyrone structure and can be synthesized by the phenylpropane pathway. Flavonoids are mostly found in esterified or glycosylated forms, and they form the basic parent nucleus of the C6-C3-C6 structure through 15 carbons (Figure 3) [44]. mRNA is translated into a polypeptide chain, which is modified and processed into four structural proteins [39,40]. The viral RNA is wrapped in the N protein and released from the cell by cytokinesis (Figure 2) [41][42][43].

Structure and Classification of Flavonoids
Flavonoids are a series of polyphenolic compounds found in various plants that have a benzo-γ-pyrone structure and can be synthesized by the phenylpropane pathway. Flavonoids are mostly found in esterified or glycosylated forms, and they form the basic parent nucleus of the C6-C3-C6 structure through 15 carbons (Figure 3) [44].

Structure and Classification of Flavonoids
Flavonoids are a series of polyphenolic compounds found in various plants that have a benzo-γ-pyrone structure and can be synthesized by the phenylpropane pathway. Flavonoids are mostly found in esterified or glycosylated forms, and they form the basic parent nucleus of the C6-C3-C6 structure through 15 carbons (Figure 3) [44]. Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].  Depending on the different substitution patterns of the rings, the position of the B ring, and the degree of oxidation of the C ring, there are six main subtypes, including flavones, flavonols, isoflavones, chalcones, flavanes, and anthocyanins (Table 1) [45].

Chemical Synthesis of Flavonoids
Flavonoids can be extracted from plants through biosynthesis and chemical synthesis. This article focuses on the chemical synthesis of flavonoids, emphasizing the synthetic routes of quercetin, baicalein, baicalin, EGCG, and luteolin.

Quercetin
The synthesis route of quercetin is as follows (Figure 4): 2% H2SO4/H2O is added to rutin 1, reacted at 80-90 °C for 4 h, and then filtered; then, the filter cake is washed with water to neutral, then recrystallized in ethanol to provide quercetin [46].

Chemical Synthesis of Flavonoids
Flavonoids can be extracted from plants through biosynthesis and chemical synthesis. This article focuses on the chemical synthesis of flavonoids, emphasizing the synthetic routes of quercetin, baicalein, baicalin, EGCG, and luteolin.

Quercetin
The synthesis route of quercetin is as follows (Figure 4): 2% H2SO4/H2O is added to rutin 1, reacted at 80-90 °C for 4 h, and then filtered; then, the filter cake is washed with water to neutral, then recrystallized in ethanol to provide quercetin [46].

Chemical Synthesis of Flavonoids
Flavonoids can be extracted from plants through biosynthesis and chemical synthesis. This article focuses on the chemical synthesis of flavonoids, emphasizing the synthetic routes of quercetin, baicalein, baicalin, EGCG, and luteolin.

Quercetin
The synthesis route of quercetin is as follows (Figure 4): 2% H2SO4/H2O is added to rutin 1, reacted at 80-90 °C for 4 h, and then filtered; then, the filter cake is washed with water to neutral, then recrystallized in ethanol to provide quercetin [46].

Chemical Synthesis of Flavonoids
Flavonoids can be extracted from plants through biosynthesis and chemical synthesis. This article focuses on the chemical synthesis of flavonoids, emphasizing the synthetic routes of quercetin, baicalein, baicalin, EGCG, and luteolin.

Quercetin
The synthesis route of quercetin is as follows (Figure 4): 2% H 2 SO 4 /H 2 O is added to rutin 1, reacted at 80-90 • C for 4 h, and then filtered; then, the filter cake is washed with water to neutral, then recrystallized in ethanol to provide quercetin [46]. routes of quercetin, baicalein, baicalin, EGCG, and luteolin.

Quercetin
The synthesis route of quercetin is as follows (Figure 4): 2% H2SO4/H2O is added to rutin 1, reacted at 80-90 °C for 4 h, and then filtered; then, the filter cake is washed with water to neutral, then recrystallized in ethanol to provide quercetin [46].

Baicalein and Baicalin
The synthesis route of baicalein is as follows ( Figure 5): Compound 3 is obtained by the reaction of trimethoxyphenol 2 with AcOH and BF3-Et2O at 60 °C for 3 h, which is further condensed with benzaldehyde for 70 h to provide compound 4. Next, compound 4 is subjected to intramolecular cyclization in the presence of I2/DMSO at 100 °C for 2.5 h to provide compound 5; then, the methyl group is removed using pyridine hydrochloride at 190 °C for 6.5 h to provide baicalein [47].

Baicalein and Baicalin
The synthesis route of baicalein is as follows ( Figure 5): Compound 3 is obtained by the reaction of trimethoxyphenol 2 with AcOH and BF 3 -Et 2 O at 60 • C for 3 h, which is further condensed with benzaldehyde for 70 h to provide compound 4. Next, compound 4 is subjected to intramolecular cyclization in the presence of I 2 /DMSO at 100 • C for 2.5 h to provide compound 5; then, the methyl group is removed using pyridine hydrochloride at 190 • C for 6.5 h to provide baicalein [47].

Quercetin
The synthesis route of quercetin is as follows (Figure 4): 2% H2SO4/H2O is added to rutin 1, reacted at 80-90 °C for 4 h, and then filtered; then, the filter cake is washed with water to neutral, then recrystallized in ethanol to provide quercetin [46].

Baicalein and Baicalin
The synthesis route of baicalein is as follows ( Figure 5): Compound 3 is obtained by the reaction of trimethoxyphenol 2 with AcOH and BF3-Et2O at 60 °C for 3 h, which is further condensed with benzaldehyde for 70 h to provide compound 4. Next, compound 4 is subjected to intramolecular cyclization in the presence of I2/DMSO at 100 °C for 2.5 h to provide compound 5; then, the methyl group is removed using pyridine hydrochloride at 190 °C for 6.5 h to provide baicalein [47].  The synthesis route of baicalin is as follows (Figure 6): Using baicalin as the starting material, the acetylation reaction is carried out in the presence of Ac 2 O and AcONa at 80 • C to obtain acetylated baicalin 6. The acetylated baicalin is refluxed with BnBr in acetone by heating in the presence of KI and K 2 CO 3 to yield the benzyl-substituted compound 7. The obtained compound 7 is removed from the benzyl group in THF by the action of Pd(OH) 2 with H 2 to provide compound 8. Additionally, compound 8 is glycosylated with brominated D-glucose in the presence of Ag 2 O at room temperature to provide glycosylated product 9. The removal of the protecting group TBDPS of compound 9 with AcOH and TBAF for 4 h provides compound 10. The subsequent oxidation of the hydroxyl group of compound 10 with TEMPO and BAIB at room temperature provides product 11. Finally, the protecting group is removed using Mg(OMe) 2 at room temperature for 3 h to provide the target compound baicalin [48]. brominated D-glucose in the presence of Ag2O at room temperature to provide glycosylated product 9. The removal of the protecting group TBDPS of compound 9 with AcOH and TBAF for 4 h provides compound 10. The subsequent oxidation of the hydroxyl group of compound 10 with TEMPO and BAIB at room temperature provides product 11. Finally, the protecting group is removed using Mg(OMe)2 at room temperature for 3 h to provide the target compound baicalin [48].

EGCG
The synthetic route of EGCG is as follows (Figure 7): Compound 12, containing allyl alcohol, is oxidized by MnO 2 at room temperature for 12 h to provide compound 13. In the presence of HBr, the aldehyde group of compound 13 is cyclized with HOCH 2 CH 2 SH to form cyclic S, O-acetal compound 14. Then, the oxidation of compound 14 with mCPBA at 0 • C for 8 h provides the oxidized S, O-acetal 15. The additional reaction with compound 15 in the presence of H 2 O is carried out with NBS to provide the bromohydrin compound 16 with stereoisomerism. The brominated alcohol of compound 16 is converted to epoxide 17 by CsCO 3 in a reaction at 0 • C for 5 h. Additionally, the phenol-containing compound 21 is reacted with compound 17 at 45 • C to provide the cis-ring-opening product 18. In the presence of DIC, the alcohol hydroxyl group of compound 18 is esterified using DMAP; subsequently, the esterified product 19 is treated with an excess of TFAA in the environment of Et 3 SiH, and DCM (1:10) is reacted first at −78 • C for 0.5 h and then at room temperature for 27 h to provide the cyclized product 20. Finally, the protecting group of compound 20 is removed using H 2 /Pd(OH) 2 at 20 atm to obtain the final product EGCG [49].

Luteolin
The synthesis route of luteolin is as follows (Figure 8): rutin 1 is used as the starting material, the protective agent Na 2 S 2 O 4 is added, and the target product luteolin is refluxed at 100 • C [50]. temperature for 27h to provide the cyclized product 20. Finally, the protecting group of compound 20 is removed using H2/Pd(OH)2 at 20 atm to obtain the final product EGCG [49].

Luteolin
The synthesis route of luteolin is as follows (Figure 8): rutin 1 is used as the starting material, the protective agent Na2S2O4 is added, and the target product luteolin is refluxed at 100 °C [50].

Anti-Inflammatory Effect
Cytokine storm is a feature of the inflammatory response induced by SARS-CoV-2 [51,52]. Flavonoids can target pathways, such as NF-κB, MAPK, ERK, and Akt, and can also reduce the release of inflammatory cytokines, which play an anti-inflammatory role [53].
A study showed that quercetin inhibited MC903-induced atopic dermatitis and improved arthritis by reducing proinflammatory factors [54,55]. Kaempferol blocked the ROS/NF-κB signaling pathway and reduced the inflammatory response in atherosclerosis [56]. In addition, kaempferol also regulated the expression of adipogenesis and reduced

Anti-Inflammatory Effect
Cytokine storm is a feature of the inflammatory response induced by SARS-CoV-2 [51,52]. Flavonoids can target pathways, such as NF-κB, MAPK, ERK, and Akt, and can also reduce the release of inflammatory cytokines, which play an anti-inflammatory role [53].
A study showed that quercetin inhibited MC903-induced atopic dermatitis and improved arthritis by reducing proinflammatory factors [54,55]. Kaempferol blocked the ROS/NF-κB signaling pathway and reduced the inflammatory response in atherosclerosis [56]. In addition, kaempferol also regulated the expression of adipogenesis and reduced lipid accumulation in CCAAT/enhancer binding protein α (CEBPA) by upregulating the mRNA expression of Pnpla2 and Lipe [57]. Janumetin prevented neuroinflammation caused by sleep deprivation and also treated atopic dermatitis caused by obesity [58,59]. Both chrysin and lignans have been shown to have preventive effects against ochratoxin A-induced gastrointestinal inflammation in vitro [60]. Oroxylin A has a therapeutic effect on collagen-induced arthritis (CIA). In a mouse model of CIA, researchers found that mice treated with Oroxylin A had significantly lower levels of inflammatory factors in their serum and reduced somatic damage caused by arthritis [61]. Rutin is reportedly effective in treating colitis. Animal research discovered that no additional medication was required, and only 0.1% rutin was added to the daily diet and fed for 2 weeks. The concentration of proinflammatory factors in the serum of the mice was lowered, and the symptoms of colitis were reduced [62]. Saeedi-Boroujeni's study reported that quercetin was able to affect the thioredoxin-interacting protein (TXNIP), thereby inhibiting NLRP3 inflammatory vesicles and achieving an inflammatory suppressive effect [63]. Clinical studies have shown that adjuvant therapy with quercetin in early COVID-19 patients significantly reduced the release of proinflammatory factors, such as TNF-β and IL-1β, and alleviated inflammation in patients with COVID-19 [43].

Antiviral Effect
Flavonoids are effective throughout the life of a virus. They can act through the inhibition of the virus cell entrance, replication of the viral gene set, translation and processing of proteins, and release of the virus from the cell [64].
It was demonstrated that both biochanin A and baicalin were able to inhibit H5N1 virus replication in A549 cells, but the mechanisms of action were different [65,66]. Both fisetin and rutin blocked viral replication by inhibiting the 3CL pro activity of enterovirus A71 [67]. Formononetin modulated COX-2/PGE 2 expression, thereby inhibiting the replication with enterovirus A71 [68]. Silymarin reportedly has anti-dengue virus activity in vitro and hepatoprotective properties for HCV infection treatment [69,70]. An in vitro study has shown that flavonoids isolated from the above-ground parts from Marcetia taxifolia are effective against herpes simplex virus, poliovirus, and hepatitis B virus [71]. The total flavonoids extracted from Robinia pseudoacacia cv. idaho showed the significant inhibition of herpes simplex virus type 1 and enterovirus type 71 with therapeutic indices of 113.8 and 46.2 [72]. It was shown that selenium functionalization with quercetin enhanced the inhibitory effect on M pro and that quercetin significantly inhibited SARS-CoV-2 infection at higher concentrations, while quercetin derivatives inhibited the viral infection at low concentrations [23]. Baicalein and baicalin were able to bind to SARS-CoV-2 RdRp, causing the RdRp to be unable to participate in the RNA replication process of the virus [73]. Several studies in vitro have shown that EGCG can prevent the RBD region of SARS-CoV-2 from binding to the ACE2 receptor, thus preventing the virus from entering cells [74,75]. Numerous studies have proved that kaempferol, catechin, rutin, hesperidin, naringenin, and luteolin all have anti-coronaviral effects.

Antidiabetic Effect
Diabetic patients infected by SARS-CoV-2 will lead to exacerbation of the disease. Reducing the effect of diabetes on COVID-19 is particularly important. Flavonoids are extremely useful in treating diabetes and diabetic complications. They can exert their therapeutic effects on diabetes by enhancing insulin secretion, regulating glucose metabolism, and reducing inflammation and oxidative stress [76][77][78].
A study showed that EGCG and quercetin reduced insulin resistance, both in vivo and in vitro, and also reduced glucose metabolism in the liver [79]. A study in a rat model of diabetes showed that EGCG improved diabetes in rats and improved streptozotocininduced complications [80]. Catechin is a naturally occurring product that has also been shown to have anti-diabetic activity. Treating rats with Eudragit particles loaded with catechins significantly reduced the concentration of blood glucose [81]. Clinical studies have found that vitamin C and rutin, when administered, significantly lowered fasting blood sugar in those with type 2 diabetes. In addition, rutin can improve neuropathy in diabetic patients [82,83]. A study exhibited that flavonoids extracted from Cistus laurifolius L. inhibited both α-glucosidase and α-amylase in vivo and vitro [84]. In a mouse model of streptozotocin-induced diabetes, the combination of Astragalus polysaccharides and Astragalus flavonoids significantly improved the function of insulin and thus exerted an anti-diabetic effect [85].
The collected evidence suggests that flavonoids can exert their antidiabetic effects through different mechanisms. However, there are no published studies about the treatment of COVID-19 diabetic patients with flavonoids.

Anticancer Effect
Studies showed that cancer patients with SARS-CoV-2 had a higher mortality rate [86]. Flavonoids can also exert antitumor effects through mechanisms such as antioxidants, COX-2 inhibition, immunomodulation, affecting cell cycle effects, apoptosis induction in cancer cells, tumor angiogenesis prevention, and telomerase activity inhibition [87,88].
In a study of the agent-sensitive LoVo cell lines and their agent-resistant LoVo/Dx subline model, baicalein and luteolin inhibited the development of colon cancer cells [89]. Baicalein also improves the effectiveness of cisplatin in human lung cancer cells [90]. Apigenin had been shown to inhibit the PI3K/Akt/mTOR pathway during viral accretion, thereby suppressing viral accretion [91]. Oroxylin A was shown to have a beneficial therapeutic effect on breast cancer by specifically binding to α-actinins 1 (ACTN1), thereby inhibiting ACTN1 expression to prevent cancer cell metastasis [92]. Oroxylin A also showed a positive inhibitory effect on lung cancer by suppressing lung cancer cell proliferation and metastasis in vivo [93]. Latifolin blocked cell growth, division, migration, invasion, and adhesion in oral squamous cell carcinoma by targeting PI10K/AKT/mTOR/p3S70K signaling [94]. EGCG and BAY11-7082 synergistically acted for the suppression of lung cancer cell proliferation both in vitro and in vivo [95].
Although SRAS-CoV-2 does not directly cause cancer, cancer patients infected with SRAS-CoV-2 have more severe symptoms and a higher lethality rate. Further investigating cancer cell inhibition would help improve COVID-19 patients' symptoms.

Anti-SARS-CoV-2 Pharmacological Effects of Quercetin
Quercetin is a flavanol compound that is widely found in various plants, mainly in the form of glycosides [96]. Studies have shown that quercetin has strong anti-inflammatory, antiviral, and immunomodulatory activities [97][98][99]. Cytokine storm is a feature of the inflammatory response induced by SARS-CoV-2 and is a major cause of death by COVID-19 [51,52]. According to relevant studies, NLRP3 inflammatory vesicles play an important role in inflammation [100]. Therefore, inhibiting NLRP3 inflammatory vesicle activation can effectively suppress the inflammatory response. Saeedi-Boroujeni's study reported that quercetin could affect the TXNIP, thereby inhibiting NLRP3 inflammatory vesicles and achieving an inflammatory suppressive effect [63]. Clinical studies have demonstrated that the adjuvant treatment of early COVID-19 with quercetin significantly reduces the viral load and release of proinflammatory factors. Meanwhile, quercetin combined with antivirals for COVID-19 reduces mortality and the length of stay [101,102]. Meanwhile, Mangiavacchi et al. have shown that selenium functionalization with quercetin enhances the inhibitory effect on M pro . According to the RT-qPCR results, quercetin at higher concentrations significantly inhibited SARS-CoV-2 infection, while quercetin derivatives inhibited the viral infection at low concentrations [23].

Anti-SARS-CoV-2 Pharmacological Effects of Baicalein and Baicalin
Baicalein and baicalin are both flavonoid compounds extracted from the dried roots from scutellaria baicalensis, which have various pharmacological effects, including antiinflammatory, antiviral, antibacterial, hepatoprotective, and choleretic [103,104]. Liu et al. investigated the antiviral activity of baicalein against SARS-CoV-2 using RT-qPCR and showed that baicalein was able to inhibit the replication of SARS-CoV-2 in Verb cells in vitro with an EC50 of 2.9 µM, SI > 172 (SI = CC50/EC50) [105]. Su et al. screened the novel inhibitors of 3CL pro using a FRET protease assay and discovered that baicalein and baicalin exhibit a significant inhibitory effect on 3CL pro [24]. In addition, Keivan Zandi et al. found that baicalein and baicalin are able to bind to SARS-CoV-2 RdRp, causing RdRp to be unable to participate in the virus ' RNA replication process; SARS-CoV-2 RdRp inhibition was first demonstrated in a study by Keivan Zandi et al. [73].

Anti-SARS-CoV-2 Pharmacological Action of EGCG
EGCG is a flavonoid extracted from green tea with various pharmacological activities, such as antibacterial, antiviral, antioxidant, and anti-inflammatory effects [106]. SARS-CoV-2 can enter host cells by binding to the ACE2 receptor via the surface S protein. Several studies in vitro have shown that EGCG can prevent the RBD region of SARS-CoV-2 from binding to the ACE2 receptor, thus preventing the virus from entering cells with a low cytotoxicity [3,74,75,107,108]. EGCG can inhibit the replication of SARS-CoV-2 by inhibiting certain key enzymes in the RNA replication process. For example, Nsp15 (U-specific endoribonuclease) can cleave the polyU sequence in viral RNA, thus interfering with the host's immune system and enabling the virus to undergo immune escape. Additionally, Nsp15 is significant in virus replication [109,110]. An in vitro study by Hong et al. exhibited that EGCG significantly inhibited the Nsp15 activity of SARS-CoV-2, with drug concentrations below 1 µg/mL completely inhibiting the activity of Nsp15 and thereby inhibiting virus replication in cells [111]. Furthermore, some studies showed that EGCG inhibits M pro in vitro, thereby inhibiting virus replication [112][113][114].

Anti-SARS-CoV-2 Pharmacological Action of Luteolin
Luteolin, mostly in the form of glycosides, exists in a variety of plants, has antiinflammatory, antiallergic, antiviral, antitumor, antibacterial, and other pharmacological activities, and is often clinically used for its anti-inflammatory effects, coughs, and expectorants [115][116][117]. In vitro studies have shown that as little as 20 µM luteolin has an inhibitory effect on 3CL pro . Additionally, luteolin also inhibits RdRp activity [25]. Xiao et al., in a SARS-CoV-2 pseudovirus experiment, discovered that luteolin is able to bind to the S protein and significantly inhibits the entry of SARS-CoV-2 into cells with an EC50 less than 7 µmol/L [118]. COVID-19 can cause a loss of smell or taste. A clinical study by L. D'Ascanio et al. showed that daily oral supplementation of palmitoylethanolamide and luteolin was able to restore the patient's sense of smell [119]. In addition, clinical studies by Lisa O'Byrne et al. also exhibited that palmitoylethanolamide and luteolin supplementation could intervene to treat olfactory dysfunction in those suffering from COVID-19 [120].

Other Flavonoids with Anti-SARS-CoV-2 Activity
Kaempferol can inhibit the activity of 3CL pro . The study by Abbas Khan and Wang Heng et al. exhibited that a 62.5-125 µg/mL concentration of kaempferol can significantly shorten the cytopathic effects (CPE) caused by Vero E6 cell infection in vitro [27].
Both hesperidin and hesperitin can inhibit the activity of TMPRSS2 and ACE2 by binding to them. Additionally, they can block the SARA-CoV-2 S protein from binding the ACE2 receptor and prevent SARA-CoV-2 from entering the cell [28]. Hesperidin also blocks the AKT pathway and inhibits Ang II-induced collagen expression and cardiac fibroblast proliferation during COVID-19 infection [121]. Clinical studies have also shown that hesperidin can reduce some of the clinical symptoms of COVID-19, such as shortness of breath, cough, decreased or even absent taste, and fever [122].
Furthermore, an in vitro study revealed that isorhamnetin also interacts with ACE2 to exert anti-SARS-CoV-2 activity [26]. It was found that naringenin exhibits potent anti-SARS-CoV-2 activity in vitro by inhibiting M pro [123,124].
The in vivo and in vitro activity studies of some flavonoid compounds are shown in Tables 2 and 3 below.

Conclusions
The COVID-19 outbreak endangers human health and livelihoods and heavily impacts global public health systems and economic development. Although there are vaccines and specific drugs to treat COVID-19, such as Paxlovid, Molnupiravir, and VV116, due to the instability of the virus, which is prone to immune escape, researchers need to investigate more drugs and options for treating COVID-19.
Flavonoids are widely found in various plants and have a significant effect on both the prevention and treatment of SARS-CoV-2. Several in vivo and in vitro studies have demonstrated that flavonoids exhibit excellent antiviral activity against SARS-CoV-2 and can inhibit SARS-CoV-2 by inhibiting key viral targets, including the ACE2 receptor, TM-PRSS2, M pro , RdRp, S protein RBD, etc. In addition, flavonoids also have an inhibitory effect on inflammation caused by SARS-CoV-2, inhibiting the production and release of various proinflammatory factors in the inflammatory response [151]. At the same time, flavonoids improve some of the clinical symptoms of COVID-19.
Although many studies have reported flavonoids' anti-SARS-CoV-2 effects, most of them are theoretical studies. Only a few in vivo and clinical studies are available. Thus, more applied experimental studies are needed to explore the drugs' safety and efficacy. Secondly, the bioavailability of the ingested compounds is limited, and how to improve the bioavailability of the compounds is also an issue to be considered. Choosing the right route of administration and preparing the drug into formulations can improve a drug's bioavailability [152]. While there are still some problems, flavonoids can undoubtedly show anti-SARS-CoV-2 effects through direct or indirect pathways. Thus, they represent a group of promising anti-SARS-CoV-2 compounds. Flavonoids have excellent medicinal potential. We are expecting more studies to explore the medicinal value of flavonoids and to develop flavonoid drugs.

Conflicts of Interest:
The authors declare no conflict of interest.